Saúl Martinez-Horta

• Doctor of Medicine
• Medical Professional at Hospital de la Santa Creu i Sant Pau

Background Cognitive impairment is a core feature of Huntington’s disease (HD), yet no disease-modifying or symptomatic interventions have demonstrated efficacy in addressing these deficits. Non-pharmacological interventions, particularly cognitive training (CT), are promising options for maintaining neural plasticity, enhancing cognition, and impr...

Background/Objectives: The treatment of tics and psychiatric comorbidities is crucial when they affect the patient’s well-being and relationships. However, the optimal pharmacological treatment (PT) tailored to each patient’s phenotype remains unclear. The primary objective of this study is to describe the clinical characteristics and treatment rec...

Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological proce...

Background Clinical diagnosis of Huntington’s disease (HD) relies on motor symptoms, but premanifest carriers show brain imaging and cognitive changes decades earlier. In this context, identifying early biomarkers is crucial. Extracellular small RNAs (sRNAs) are promising biomarkers due to their sensitivity to pathobiological processes. Easily foun...

Background The brain systems involved in encoding reward-related signals and in reward prediction are compromised in Huntington’s disease (HD). Few studies have explored the integrity of these processes and their impact on behavior. Methods 49 gene mutation carriers (preHD: n=21; HD: n=28) and 21 controls were recruited. We designed a decision-mak...

Background Recent studies have shown abnormal tau accumulation in the brains of Huntington's disease (HD) patients, highlighting tau protein dysregulation as a key aspect of its pathogenesis. Particularly, the role of 4R tau isoforms has been connected to HD progression and cognitive decline. Although tau protein levels have been examined in cerebr...

Objective This study aims to investigate correlations between mHtt and NfL levels and MRI findings in individuals at different stages of HD, including presymptomatic and symptomatic individuals. Background Biomarkers in Huntington's disease (HD) are crucial for understanding disease progression and developing effective therapies. Cerebrospinal flu...

Background Impairment of the endosomal/lysosomal system is present in HD. Indeed, we previously described reduced levels of Alix, a protein associated with this system and neuronal death, in postmortem HD brains. Aims Here, we investigated whether alterations in Alix protein levels could be detected in cerebrospinal fluid (CSF) of HD mutation carr...

Background In Huntington’s disease (HD), language disturbances have traditionally focused on motor, syntactic and speech organization defects, but little is known about semantic processing integrity. We aimed to explore semantic processing in manifest HD by means of neurophysiological indexes and its association with other parameters derived from l...

Background Frontal-related behavioral and cognitive symptoms, including perseveration, irritability and executive dysfunction, are characteristics of Huntington’s disease (HD). Although these symptoms can lead to maladaptive and reckless behaviors, few studies have delved into the prevalence, correlates and phenomenology of violent and criminal beh...

Background Progression and age of onset are inversely linked to abnormal CAG repeat length in Huntington's disease (HD). However, the disparity in clinical outcomes among patients with equal repetitions suggests that additional variables affect HD. Tau protein, encoded by the microtubule-associated protein tau (MAPT) gene, exhibits an inversion pol...

Background Recent evidence indicates that beyond the accumulation of mutant Huntingtin protein (mHTT), tau and other proteinopathies are associated with the clinical phenotypes of Huntington's disease (HD). Postmortem studies have suggested the presence of amyloid-beta and phosphorylated tau co-pathology in the HD brains,¹ but reports based on CSF...

Thiamine (Vit B1) deficiencies (acquired or genetic) result in encephalopathies, some of which affect particularly the striatum, like that by mutations of the brain endothelium thiamine transporter (SLC19A3=ThTr2; OMIM #607483, Biotin and thiamine-responsive basal ganglia disease). Transcriptomic analyses of brain tissue from Huntington’s disease (...

Background Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease. Objective This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes. Methods In this cross‐sectional study, we measured skin tau levels using enz...

Objective: Cognitive impairment in Parkinson's disease (PD) can show a very heterogeneous trajectory among patients. Here, we explored the mechanisms involved in the expression and prediction of different cognitive phenotypes over 4 years. Methods: In 2 independent cohorts (total n = 475), we performed a cluster analysis to identify trajectories o...

Objective The clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity...

Parkinson disease (PD) psychosis (PDP) is a spectrum of illusions, hallucinations and delusions that are associated with PD throughout its disease course. Psychotic phenomena can manifest from the earliest stages of PD and might follow a continuum from minor hallucinations to structured hallucinations and delusions. Initially, PDP was considered to...

Hypomimia is a frequent manifestation in Parkinson's disease (PD) that can affect interpersonal relationships and quality of life. Recent studies have suggested that hypomimia is not only related to motor dysfunction but also to impairment in emotional processing networks. Therefore, we hypothesized that the severity of hypomimia could be associate...

Background Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to dynamics in motor and cognitive large‐scale networks are not well established. Objective To investigate changes in dynamic and static large‐scale networks...

Background Frontal lobe signs in progressive supranuclear palsy (PSP) are prevalent and occur early in the disease. Although they are recognized in clinical practice, studies are needed to systematically investigate them for an in‐depth understanding of the neurological substrate and their potential prognostic implications in the disease. Objectiv...

Despite the advances in the understanding of Huntington's disease (HD), there is the need for molecular biomarkers to categorize mutation-carriers during the preclinical stage of the disease preceding the functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological...

La percepción del tiempo juega un papel central dentro del conjunto de procesos que rigen la construcción de la realidad que experimentamos. A pesar de ser un fenómeno cotidiano, seguimos sin disponer de un modelo que lo explique en su totalidad. Pero tanto las aproximaciones basadas en modelos neurocognitivos como el estudio de la función normal y...

Background Progressive cognitive decline is an inevitable feature of Huntington’s disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods We collected data from a cohort of 180 positive g...

Background: Cognitive impairment is a central feature of Huntington's disease (HD), but it is unclear to what extent more aggressive cognitive phenotypes exist in HD among individuals with the same genetic load and equivalence in other clinical and sociodemographic variables. Methods: We included Enroll-HD study participants in early and early-m...

Individuals with pre‐manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word‐problems. However, the neural correlates of these deficits in HD are poorly understood. We explored the structural (gray‐matter volume; GMV) and metabolic (18F‐FDG PET; SUVr) brain correlates of arithmetic performance using t...

Cognitive decline and hallucinations are common and debilitating non-motor symptoms, occurring during later phases of Parkinson's disease (PD). Minor hallucinations (MH), appear at early phases and have been suggested to predict cognitive impairment in PD, however, this has not been well-established by clinical research. Here, we investigated wheth...

Background: Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 H...

Background Cognitive and neuropsychiatric disturbances in Parkinson's disease are as common and as disabling as its well-known motor symptoms. Even though several neural substrates for these symptoms have been suggested, to which extent these symptoms reflect cortical neurodegeneration in Parkinson’s disease remains to be fully elucidated. Methods...

Background Although white matter (WM) abnormalities and subcortical iron accumulation are causal factors of neurodegeneration in Huntington’s disease (HD), their specific role is not clear yet. Aims: To understand the dynamics of the physiopathology process underlying in HD by using a multimodal temporo-spatial characterization of WM tracts (micros...

Background Huntington’s disease (HD) is an inherited autosomal dominant disease characterized by progressive degeneration of the striatum and the cerebral cortex caused by a mutation in the Huntingtin gene comprising an expansion of a CAG repeat. Mutant huntingtin accumulates in endosomal compartments and triggers the activation of the endo-lysosom...

Background Huntington’s Disease (HD) is a neurodegenerative disorder characterized by cognitive, motor, and neuropsychiatric manifestations. Oxytocin is a neuropeptide studied for its role as a neuromodulator regulating multiple behaviors linked to social cognition. Genetic variation of oxytocin receptor (OXTR) might interact in the etiology and de...

A previously healthy woman began to present recurrent episodes of reduplicative paramnesia within her home and later structured visual hallucinations. The case was initially oriented as an incipient vascular dementia. Detailed anamnesis and neuropsychological examination suggested a rapidly progressive pattern of neuropsychological deficits mostly...

Background Minor hallucinations in Parkinson's disease are associated with connectivity changes in attentional networks and increased risk of structured hallucinations. However, the clinical translation of these abnormalities in attention processes is not well-defined, and commonly used neuropsychological tests are not able to detect significant de...

Objectives: To evaluate if the feedback related negativity (FRN) -a neurophysiological marker of incentive processing- can be used to predict the development of impulse control disorders (ICD) in Parkinson's disease (PD) METHODS: Longitudinal cohort of consecutive non-demented Parkinson's disease patients with no ICD history. We recorded FRN signa...

Congenital heart defects (CHD) are the most prevalent malformations in the newborn. They affect 1% of newborns with moderate to severe CHD in about 6 of every 1,000 live births (Hoffman & Kaplan, 2002). Due to advances in diagnostic techniques and surgical management, the survival rates of patients with complex CHD have increased. However, alterati...

Background Patients with Huntington’s disease (HD) exhibit a variable predominance of cognitive, behavioral and motor symptoms. A specific instrument focusing on the impact of cognitive impairment in HD over functional capacity is lacking. Objective To address the need for a brief and specifically developed HD questionnaire able to capture functio...

Background and purpose: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. Methods: The clinical...

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive, motor, and neuropsychiatric manifestations. Oxytocin is a neuropeptide studied for its role as a neuromodulator regulating multiple behaviors linked to social cognition. Genetic variation of oxytocin receptor (OXTR) might interact in the etiology and...

Background: Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofila...

Background Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective We studied the effects of safinamide on apathy in PD. Methods Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented...

Background Apathy represents a core neuropsychiatric symptom in Parkinson’s disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated w...

Mild cognitive impairment in Parkinson’s disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI...

Purpose Huntington’s disease (HD) is a monogenic neurodegenerative disease with no effective treatment currently available. The pathological hallmark of HD is the aggregation of mutant huntingtin in the medium spiny neurons of the striatum, leading to severe subcortical atrophy. Cortical degeneration also occurs in HD from its very early stages, al...

Background Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive. Objective To characterize the cortical structural correlates of homocysteine le...

Background Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson’s disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods Using a standard approach for the assessment of global cognition in PD and controlling for the effects of...

Female Huntington’s disease (HD) patients have consistently shown a faster clinical worsening than male, but the underlying mechanisms responsible for this observation remain unknown. Here, we describe how sex modifies the impact of neurodegeneration on brain atrophy and clinical severity in HD. Cerebrospinal fluid neurofilament light chain (NfL) l...

Background: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. Objective: We aimed to profile changes in large-scale cognitive networks in premanife...

Green oat extracts have been used for centuries in traditional medicine in view of their supposed beneficial effects on cognition and mood. Recently, a specific green oat formulation (Neuravena®) showed to have significant bioactive compounds potentially associated with the enhancement of processing speed, working memory and attention. The main aim...

Background: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington's disease (HD). Objective: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations betw...

Background Although several progressive supranuclear palsy (PSP) phenotypes have recently been described, studies identifying cognitive and neuropsychiatric differences between them are lacking. Methods An extensive battery of cognitive and behavioural assessments was administered to 63 PSP patients, 25 PD patients with similar sociodemographic cha...

Background HD is a suitable model to monitor the whole neurodegeneration process. Huntington’s disease (HD) affects primarily the striatum, but loss of white matter (WM) integrity and iron homeostasis disruption have been also described. These anomalies together with metabolite profiles could unveil the pathophysiologic mechanisms involved. Aims T...

Background While Huntington’s disease (HD) is diagnosed by motor onset, psychiatric disturbances may present years prior to formal diagnosis, bearing a significant burden on daily functioning. However, there is great inter-individual heterogeneity in psychiatric expression and evolution over time. As such, the present study strives to discern longi...

Background: Empathy is a multidimensional construct and a key component of social cognition. In Huntington's disease (HD), little is known regarding the phenomenology and the neural correlates of cognitive and affective empathy, and regarding how empathic deficits interact with other behavioral and cognitive manifestations. Objective: To explore...

Aim To determine if there are differences in terms of neurophysiology and neurocognitive functioning a group of type 1 diabetes (T1D) patients in terms of hypoglycaemia awareness. Methods 27 patients with T1D were classified according to Clarke score as having impaired awareness of hypoglycaemia (IAH; n=11) or normal awareness to hypoglycaemia (NA...

Background: Apathy, a common neuropsychiatric disturbance in Huntington's disease (HD), is subserved by a complex neurobiological network. However, no study has yet employed a whole-brain approach to examine underlying regional vulnerabilities that may precipitate apathy changes over time. Objectives: To identify whole-brain gray matter volume (...

Hallucinations in Parkinson’s disease (PD) are disturbing and frequent non-motor symptoms and constitute a major risk factor for psychosis and dementia. We report a robotics-based approach applying conflicting sensorimotor stimulation, enabling the induction of presence hallucinations (PHs) and the characterization of a subgroup of patients with PD...

Cognitive deficits are common in Parkinson's disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial in achieving fast and efficient comprehension, and it may be negatively impacted by cognitive dete...

Objectives To explore and quantify systematically the ocular abnormal movements present in progressive supranuclear palsy (PSP) from the early stages, to assess the ability of this standardized examination in the differential diagnosis of PSP from Parkinson’s disease (PD), and to compare in more detail oculomotor disturbances between PSP variants....

Introduction Huntington’s disease is a severe neurodegenerative disorder with no effective treatment. Minimally-invasive biomarkers such as blood neurofilament light chain (NfL) in HD are therefore needed to quantitatively characterize neuronal loss. NfL levels in HD are known to correlate with disease progression and striatal atrophy, but whether...

In Huntington’s disease (HD), irritability and aggressive behavior represent highly prevalent and disabling neuropsychiatric symptoms. However, their structural brain correlates have not been extensively explored. Here, we rated the severity of irritability and aggression (IAs) using the Problem Behaviors Assessment for HD (PBA-s) in 31 early HD pa...

The original version of this article unfortunately contained a mistake.

Striatal dopamine transporter (DAT) uptake assessment through I¹²³-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the...

Cognitive deficits are common in Parkinson’s disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial in achieving fast and efficient comprehension, and it may be negatively impacted by cognitive dete...

Context Type 1 Diabetes (T1D) is associated with an increased risk of cognitive decline, where severe hypoglycaemia (SH) and impaired awareness of hypoglycaemia (IAH) may play a role. While there is evidence of a possible association between IAH and brain damage, the potential brain changes remain poorly characterized by magnetic resonance imaging...

Background Chronic levodopa treatment in Parkinson’s disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous infusion of levodopa/carbidopa intestinal gel (LCIG) in advanced PD reduces motor fluctuations. However, differences in their effect on acute non-motor changes were not f...

Background and purpose Well‐structured hallucinations in Parkinson’s disease (PD) are associated with poor prognosis and dementia. However, the predictive value of minor psychotic phenomena in cognitive deterioration is not well known. Cross‐sectional studies have shown that PD patients with minor hallucinations have more severe cortical atrophy th...

About 20% of type 1 diabetes (T1D) patients have impaired awareness of hypoglycemia (IAH). IAH represents a risk factor for severe and recurrent hypoglycemic events, which can lead to brain damage. As no effective treatments are currently available to prevent IAH in this population, characterizing the set of brain alterations associated with IAH ma...

Background: Huntington's disease (HD) is a fatal genetic neurodegenerative disorder with no effective treatment currently available. Progressive basal ganglia and whole-brain atrophy and concurrent cognitive deterioration are prototypical aspects of HD. However, the specific patterns of brain atrophy underlying cognitive impairment of different se...

Background Impulse control disorders (ICD) are a common and disrupting complication of Parkinson’s disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. Methods In this work we studied brain metabolism using brain ¹⁸F-FDG-PET. We performed a case-control...

Introduction Impaired awareness of hypoglycemia (IAH) is a common complication in patients with type-1 diabetes (T1D). IAH is a major risk factor for severe hypoglycemic events, leading to adverse clinical consequences and cerebral damage. Non-invasive, cost-effective, and logistically efficient biomarkers for this condition have not been validated...

Hallucinations in Parkinson's disease (PD) are one of the most disturbing non-motor symptoms, affect half of the patients, and constitute a major risk factor for adverse clinical outcomes such as psychosis and dementia. Here we report a robotics-based approach, enabling the induction of a specific clinically-relevant hallucination (presence halluci...

Background Cognitive impairment is an essential feature of Huntington’s disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking.Objectives We aimed to explore the utility of the Parkinson’s disease-Cognitive Rating Scale (PD-CRS) for the...

Introduction: Memory alterations are common in Parkinson's disease (PD) patients but the mechanisms involved in these deficits remain poorly understood. The study aims to explore the profile of episodic memory deficits in non-demented early PD patients. Methods: We obtained neurological, cognitive and behavioral data from 114 PD patients and 41 hea...

Background Impulsivity is an aspect of personality and a major component of multiple neuropsychiatric conditions. In Parkinson’s disease, it has been associated with the expression of impulse control disorders, a highly prevalent non‐motor complication. Even though multiple tests of impulsivity have been used in this context, the impact of test cho...

Introduction Cognitive impairment and dementia are highly prevalent non-motor complications in Parkinson's disease (PD) with deleterious consequences for patients and caregivers. With no treatment currently available, finding and validating minimally-invasive biomarkers of neurodegeneration in this population represents an urgent need for clinical...

We have discovered an error in the Table in our article “Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease.” The Table contains a typographical error. In the column headed “PD-Not Depressed,” the number of women should be 101 (not 104). The associated percentages and statistics were based on the correct number and there...

Background: The C allele of the rs11136000 genetic variant of the clusterin gene has been associated with increased risk of Alzheimer's disease. However, a comprehensive characterization of the role of this genetic variant in early cognitive deterioration in PD is lacking. Methods: Using the Parkinson's Progression Markers Initiative database, w...

Progressive striatal atrophy has long been considered the pathological hallmark of Huntington’s disease (HD), but is it now recognized that malfunction and degeneration of posterior-cortical territories are also prominent characteristics of the disease. The limited knowledge about the functional impact of these posterior-cortical changes could be p...

Cognitive impairment and dementia in Parkinson's disease (PD) are highly disabling non-motor symptoms with no effective treatment currently available. As cortical degeneration is thought to be involved in the development of these comorbidities, novel imaging biomarkers capable of detecting early cortical deterioration are needed. Recently, an incre...

Background and purpose: Huntington disease is a devastating genetic neurodegenerative disorder for which no effective treatment is yet available. Although progressive striatal atrophy is its pathologic hallmark, concomitant cortical deterioration is assumed to occur, but it is poorly characterized. Our objective was to study the loss of cortical i...

Objectives: To longitudinally evaluate the role of depression in the development of impulse control disorders (ICD) in Parkinson's disease (PD) patients. Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) we included PD patients without ICD at baseline according to the Questionnaire for Impulsive-Compulsive Disorders...

Understanding on the clinical features and neural mechanisms leading to cognitive impairment and dementia in Parkinson’s disease (PD) has notably increased. At time of diagnosis, nearly all PD patients present some degree of cognitive impairment not enough severe as to significantly affect functional independence. However, even mild cognitive chang...

Background: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. Objectives: To disentang...

Introduction: Cognitive impairment and behavioral disturbances are common findings in Parkinson’s disease (PD). Despite initially being considered late complications of the disease, it is currently accepted that almost all PD patients will exhibit cognitive and behavioral abnormalities from the early and even the premotor stages of the disease. Are...

The brain-derived neurotrophic factor (BDNF) val66met polymorphism has been suggested to modulate cognitive deterioration in Parkinson's disease (PD). In particular, the val/val genotype has been recently suggested to increase the risk of cognitive decline in this population. However, to date, little is known about the underlying brain alterations...

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored t...